The "Down Syndrome Critical Region" Is Sufficient in the Mouse Model to Confer Behavioral, Neurophysiological, and Synaptic Phenotypes Characteristic of Down Syndrome
The "Down Syndrome Critical Region" Is Sufficient in the Mouse Model to Confer Behavioral, Neurophysiological, and Synaptic Phenotypes Characteristic of Down Syndrome
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DOI：
10.1523/jneurosci.1547-09.2009
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发表时间：
2009-05-06
影响因子：
5.3
通讯作者：
Mobley, William C.
中科院分区：
文献类型：
--
作者：
Belichenko, Nadia P.;Belichenko, Pavel V.;Mobley, William C.
唐氏综合征（DS）可以在小鼠中建模，小鼠染色体16节段性三体。Ts65Dn和Ts1Cje小鼠模型已被用于研究DS的神经生物学表型，包括认知能力的变化，诱导长时程增强（LTP）在筋膜齿状回（FD），树突棘的密度和大小，和突触的结构。为了探索这些表型的遗传基础，我们检查了Ts1Rhr小鼠，这些小鼠是Ts65Dn和Ts1Cje小鼠中三倍的基因的一个小子集的三体。Ts1Rhr中的33个三体基因代表了“DS关键区域”，该区域曾被预测足以产生大多数DS表型。我们发现显着的变化，在一个开放的领域测试，一种新的物体识别测试和T型迷宫任务。与Ts65Dn和Ts1Cje小鼠一样，只有阻断GABA依赖的抑制性神经传递后，才能诱导Ts1Rhr FD的LTP。此外，广泛扩大的树突棘和密度降低的棘在FD中被保存在Ts1Rhr。48个表型中有20个在Ts1Rhr和2N对照之间显示出显著差异。我们的结论是，DS的重要神经生物学表型特征是保守的Ts1Rhr小鼠。这些数据支持这样的观点，即由于Ts1Rhr三体区段中基因的剂量效应而发生具有生物学意义的三体表型，并且增加的剂量足以产生这些变化。现在的研究阶段是破译在创造这些表型中发挥突出作用的基因。
Down syndrome (DS) can be modeled in mice segmentally trisomic for mouse chromosome 16. Ts65Dn and Ts1Cje mouse models have been used to study DS neurobiological phenotypes including changes in cognitive ability, induction of long-term potentiation (LTP) in the fascia dentata (FD), the density and size of dendritic spines, and the structure of synapses. To explore the genetic basis for these phenotypes, we examined Ts1Rhr mice that are trisomic for a small subset of the genes triplicated in Ts65Dn and Ts1Cje mice. The 33 trisomic genes in Ts1Rhr represent a "DS critical region" that was once predicted to be sufficient to produce most DS phenotypes. We discovered significant alterations in an open field test, a novel object recognition test and in a T-maze task. As in Ts65Dn and Ts1Cje mice, LTP in FD of Ts1Rhr could be induced only after blocking GABAA-dependent inhibitory neurotransmission. In addition, widespread enlargement of dendritic spines and decreased density of spines in FD were preserved in Ts1Rhr. Twenty of 48 phenotypes showed significant differences between Ts1Rhr and 2N controls. We conclude that important neurobiological phenotypes characteristic of DS are conserved in Ts1Rhr mice. The data support the view that biologically significant trisomic phenotypes occur because of dosage effects of genes in the Ts1Rhr trisomic segment and that increased dosage is sufficient to produce these changes. The stage is now set for studies to decipher the gene(s) that play a conspicuous role in creating these phenotypes.